A subject of the present invention is a novel process for the preparation of bicyclic compounds and the use of this process as an intermediate stage in the preparation of a compound which inhibits the interleukin-1 beta converting enzyme (ICE).
The compound of formula (I) as defined below, in which R represents a terbutyl radical and the amine is protected in the form of phthalimido, is described in the Patent EP 94095. This compound of formula (I) is also used for the preparation of the compound of formula (V) having an inhibitory activity on the interleukin-1 beta converting enzyme described in the International Application WO 97/22619.
One of the objectives of the invention is to find a novel process of obtaining the compounds of formula (I).
Therefore a subject of the invention is a process for the preparation of the compounds of formula (I) 
in which R represents a hydrogen atom, an alkyl, aryl or aralkyl radical containing up to 18 carbon atoms and the amine function can be free or protected, starting from a compound of formula (IA) 
in which R has the same meaning as previously and the amine function can be free or protected,
characterized in that the cyclization is carried out in a basic medium and in the presence:
of a derivative of phosphonic acid of formula (P1):
P(xe2x95x90Z)(X1)(X2)(X3)
in which Z is a sulphur or oxygen atom, X1 represents a halogen atom, X2 and X3, identical or different, represent a halogen atom, an alkyloxy radical containing 1 to 6 carbon atoms, an aryloxy radical containing 6 to 12 carbon atoms or an arylalkyloxy radical containing 7 to 15 carbon atoms,
or of a trimer of formula (P2) 
R preferably represents a hydrogen atom, a methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tertbutyl, benzyl, phenyl or naphthyl radical and quite particularly methyl, ethyl and tertbutyl.
When the amine function is protected, the protection can be done according to the standard methods known to a person skilled in the art.
The amine function can be protected in the form of an xe2x80x94NR1R2 radical in which
either R1 represents a 
radical, Ra, Rb, Rc and Rd representing an alkyl or aryl radical containing up to 18 carbon atoms or a mono or polycyclic radical containing one or more heteroatoms, X representing a hydrogen atom, an alkyl radical containing up to 8 carbon atoms or an aryl radical containing up to 14 carbon atoms, and R2 represents a hydrogen atom,
or R1 and R2 together form a mono or polycyclic radical containing 1 or more heteroatoms. The amine can thus be protected in the form of a phthalimido 
or also in the form of the 
radical.
Preferably, the amine is protected in the form of a phthalimido.
Among the derivatives of phosphonic acid of formula P(xe2x95x90Z)(X1)(X2)(X3), it is in particular the following derivatives:
(Cl)P(O)(Ph)2, (Cl)2P(O)(OPh)2, (Cl)P(O)(OEt)2, (Cl)2P(O)(OEt)2, POCl3, POBr3 and P(S)Cl3.
The cyclization reaction is preferably carried out in the presence of POCl3 or POBr3 and the base is in particular an organic base, for example triethylamine, pyridine or 2,6-lutidine.
A more particular subject of the invention is the process as described previously in which the trihalogenophosphonic acid is POCl3.
A more particular subject of the invention is the process as described previously in which the trihalogenophosphonic acid is POBr3.
A more particular subject of the invention is the process as described previously in which the base is chosen from pyridine or 2,6-lutidine.
A more particular subject of the invention is the process as defined previously characterized in that the cyclization temperature is comprised between 70 and 80xc2x0 C.
A more particular subject of the invention is the process as defined previously characterized in that the solvent is dichloroethane.
The compound of formula (IA) is in the form of a mixture of SS and SR diastereoisomers or in the form of the SR diastereoisomer.
The compound of formula (I) is in the form of a mixture of SS and SR diastereoisomers or in the form of the SR diastereoisomer.
A subject of the invention is also a process for the preparation of the compound of formula (I) in racemic or optically active (Iopt) form, comprising the cyclization process as described above, and characterized in that it comprises the following successive stages:
a) A compound of formula (II) 
xe2x80x83in which R is as defined previously and Hal represents a halogen atom, is subjected to the action of a compound of formula (III) 
xe2x80x83in which Aryl represents an aryl radical containing up to 14 carbon atoms, in order to obtain the compound of formula (IV) 
xe2x80x83in the form of a mixture of S and R stereoisomers,
b) the compound of formula (IV) is subjected to the action of an anhydride of formula (F) 
xe2x80x83the amine function being in protected or non-protected form, while carrying out a deprotection by hydrogenolysis, in order to obtain the compound of formula (IA) 
xe2x80x83as defined above,
c) the compound of formula (IA) is subjected to the action of a derivative of phosphonic acid (P1) or (P2) as defined above, in the presence of a base, in order to obtain the compound of formula (I) as defined above 
d) if appropriate, the amine function is deprotected in order to obtain the compound of formula (I) in which the amine function is not protected,
e) if appropriate, the compound of formula (I) in the SS+SR or SR form is subjected to the action of a deracemization and/or epimerization agent in order to obtain the compound of formula (Iopt) corresponding to the SS diastereoisomer, 
f) if appropriate, the amine function is deprotected in order to obtain the compound of formula (Iopt) in which the amine function is not protected.
In a preferred embodiment:
Hal represents a chlorine atom;
R represents an alkyl radical containing 1 to 4 carbon atoms;
Aryl represents a phenyl or naphthyl radical,
Compound (F) is N-phthaloyl-L-glutamic anhydride 
The amine function of the compounds of formulae (IA), (I) or (Iopt) is in protected form and in particular in phthalimido form;
The reaction between the compounds of formula (II) and the compounds of formula (III) takes place in the presence of a base for example in the presence of an alkaline carbonate such as potassium carbonate;
The deprotection by hydrogenolysis is carried out according to standard conditions known to a person skilled in the art, for example the hydrogenolysis agent is hydrogen in the presence of palladium on carbon;
The deracemization and/or epimerization agent is a base, more especially a strong base, for example an alkaline or alkaline-earth alcoholate such as sodium or potassium methylate, sodium or potassium terbutylate or a lithiated amine such as LDA;
The action of a deprotection agent of the amine can be carried out in particular by the action of a hydrazine.
A quite particular subject of the invention is the process as defined previously in which (F) is the anhydride of phthaloyl glutamic acid.
A quite particular subject of the invention is the process as defined previously in which the amine function of the compounds of formulae (IA), (I) or (Iopt) is protected in the form of a phthalimido group.
A quite particular subject of the invention is the process as defined previously in which, within the compounds of formula (II), (IV), (IA), (I) and (Iopt), R is a methyl, ethyl or tertbutyl radical.
A quite particular subject of the invention is the process as defined previously in which the compound of formula (I) is ethyl 9-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-3,4,7,8,9,10-hexahydro-6,10-dioxo-6H-pyridazino-[1,2-a][1,2]diazepine-1-carboxylate: 
A quite particular subject of the invention is the process as defined previously in which the compound of formula (Iopt) is ethyl-(1S-cis)-9-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-3,4,7,8,9,10-hexahydro-6,10-dioxo-6H-pyridazino-[1,2-a][1,2]diazepine-1-carboxylate: 
The compounds of formula (I) can in general be used for the synthesis of medicaments as indicated in the Patent EP 94095. The compounds of formulae (II) and (III) and (F) are known and can be prepared according to the experimental method described below.
A subject of the invention is also the use of the process as defined above as an intermediary stage for the preparation of a compound of formula (V) 
via the compound of formula (Iopt) as defined previously, characterized in that this process comprises the stages of the process for the preparation of the compounds of formula (Iopt) starting from the compounds of formula (II) as defined previously.
A subject of the invention is also the use as defined above, characterized in that the compound of formula (Iopt) is ethyl (1S-cis)-9-(1,3-dihydro-1,3-dioxo-2H-isoindol-2yl)-3,4,7,8,9,10-hexahydro-6,10-dioxo-6H-pyridazino-[1,2-a][1,2]diazepine-1-carboxylate 
A subject of the invention is also the use of the process as defined above as an intermediate stage of the overall preparation process for the compounds of formula (I) and (Iopt) as defined previously.
Finally, a subject of the invention, as an intermediate compound, is the compound of formula (IA) as defined previously.
The following examples illustrate the invention without however limiting it.
Preparation of bis(phenylmethyl) 1,2-hydrazinecarboxylate
1.5 liters of methanol and 25 g of hydrazine monohydrate at 80% are placed under nitrogen. The reaction medium is cooled down to 0xc2x0 C. and then 75 g of benzyl chloroformate and a solution of 93 g of sodium carbonate in 1100 ml of demineralized water are introduced. The reaction mixture is maintained at 0xc2x0 C. for 1 hour, followed by separating and washing by displacement with a mixture of 100 ml of methanol and 100 ml of water, then washing by displacement with 500 ml of water at 0xc2x0 C. After drying 107.6 g of sought product is obtained.
Preparation of N-phthaloyl-L-glutamic Anhydride D (+)
2-tetrahydro-2,6-dioxo-2H-pyran-3-yl-1H-isoindole-1,3(2H)-dione (R)
Stage a: N-phthaloyl-L-glutamic Acid
2-(1,3-dihydro-1,3-dioxo-2H-isoindole-2-yl)-pentanedioic acid (2S)
10 g of L-glutamic acid then 16 g of N-carbethoxyphthalimide (Nefkens reagent, commercial) are added to a solution of 14.4 g of sodium carbonate in 180 ml of water. Agitation is carried out at ambient temperature for 2 hours followed by extraction with ethyl acetate. The organic phase is evaporated under reduced pressure until a dry extract is obtained and 2.74 g of crude product is obtained. Washing is carried out with sodium bicarbonate, then after returning to the acid and extraction with ethyl acetate, 370 mg of expected product and H2Nxe2x80x94CO2Et are isolated. Moreover, the aqueous phase is adjusted to pH=2 with 36% hydrochloric acid at a temperature lower than 5xc2x0 C. then extracted with ethyl acetate, washed with a saturated solution of sodium chloride, dried, filtered and concentrated under reduced pressure until 22.7 g of expected product is obtained in the form of an oil.
Mass spectrum (Mxe2x88x92H)xe2x88x92=276xe2x88x92
Infrared (Nujol): 1775 cmxe2x88x921(m), 1720 cmxe2x88x921 (F, complex): CO 1611 cmxe2x88x921: Aromatic
Stage b:
160 ml of tetrahydrofuran is added and 18.6 g of DCC (1,3-Dicyclohexyl-carbodiimide) in solution in 55 ml of tetrahydrofuran is added dropwise over 30 minutes to the product obtained in stage a). Agitation is carried out for 1 hour at 15-17xc2x0 C., followed by filtering, rinsing with tetrahydrofuran, evaporating under reduced pressure until a dry extract is obtained which is taken up in isopropyl oxide. After agitation for 30 minutes, filtering is carried out followed by washing and drying. 14.98 g of expected product is obtained.
xcex1D=xe2x88x9252.63
1H NMR (DMSO) 2.12 (m, 1H); 2.61 (m, 1H); 2.98 (dm, 1H); 3.16 (ddd, 1H); 5.48 (dd, 1H); 7.82 (m,  greater than 4H)